Methods and apparatus for flow restoration

ABSTRACT

Methods for restoring blood flow in occluded blood vessels using an apparatus having a self expandable distal segment that is pre-formed to assume a superimposed structure in an unconstrained condition but can be made to take on a volume-reduced form making it possible to introduce it with a microcatheter and a push wire arranged at the proximal end, with the distal segment in its superimposed structure assuming the form of a longitudinally open tube and having a mesh structure of interconnected strings or filaments or struts. In a preferred embodiment, the distal segment has a tapering structure at its proximal end where the strings or filaments or struts converge at a connection point.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of International ApplicationNo. PCT/US2009/034774, filed on Feb. 20, 2009, which claims the benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application Ser. No.61/030,838 filed on Feb. 22, 2008, each of which is hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods and apparatus for quickly orimmediately restoring blood flow in occluded blood vessels, particularlyoccluded cerebral arteries. Furthermore, the present invention relatesto the application of such apparatus for thrombus removal and/orthrombus dissolution.

BACKGROUND OF THE INVENTION

Current technology for treating cerebral arteries occluded by thrombusmay take hours to reestablish flow in the artery. Furthermore, knownapparatus and methods for treating cerebral thrombus may be ineffectiveor only partially effective at resolving thrombus, and may additionallyresult in distal embolization or embolization of uninvolved arteries.The risk and degree of permanent neurological deficit increases rapidlywith increased time from onset of symptoms to blood flow restoration.

SUMMARY OF THE INVENTION

The invention is directed to methods of restoring localized blood flowin a vascular site occluded with a thrombus. It is contemplated that themethods of the invention improve the speed and effectiveness ofrevascularization of cerebral arteries occluded by a thrombus.

In one embodiment, methods and apparatus are provided to createimmediate (or restore) blood flow in the occluded artery upon deploymentof the apparatus. In one aspect, a self-expandable apparatus isdelivered to a site that is radially adjacent to the thrombus and theapparatus is expanded thereby restoring flow.

In another embodiment, the invention is directed to methods andapparatus that restore blood flow in the blood vessel that is occludedwith a thrombus, with an associated increased efficiency in dislodgingthe thrombus from the vessel and removing the thrombus. In thisembodiment, a self-expandable apparatus is delivered to a site that isradially adjacent to the thrombus and then expanded. The expandedapparatus then restores flow, which flow assists in dislodging thethrombus from the vessel wall. In one embodiment, the apparatus engagesthe thrombus and the thrombus can then be removed from the site ofocclusion.

In yet another embodiment, the invention is directed to methods andapparatus that restore blood flow in the occluded artery, with anassociated increased efficiency in dissolving part or all of thethrombus from the vessel and optionally retrieval of the apparatus. Inthis embodiment, a self-expandable apparatus is delivered to a site thatis radially adjacent to the thrombus and then expanded. Once expanded,the apparatus then restores flow to the occluded site and this increasedflow may dissolve or partially or substantially dissolve the thrombusand the apparatus-thrombus mass is then removed from the formerlyoccluded site.

In still yet another embodiment, the invention is directed to methodsand apparatus that restore blood flow in the occluded artery, with anassociated increased efficiency in dissolving part or all of thethrombus from the vessel and implantation of a portion of the apparatus.In this embodiment, the apparatus engages (or implants in or integrateswith) at least a portion of the thrombus providing a removable,integrated apparatus-thrombus mass. The removable, integratedapparatus-thrombus is removed from the site of occlusion.

In some embodiments, the method of the invention is directed to a methodfor imaging restoration of blood flow in a blood vessel occluded with athrombus. This method comprises: a) acquiring an image of aself-expandable apparatus placed radially adjacent to a thrombus; and b)acquiring an image of expanding the apparatus thereby restoring bloodflow.

In another embodiment, the method of the invention is directed to amethod for imaging partially or substantially dissolving a thrombuslodged in a blood vessel. This method comprises: a) acquiring an imageof a self-expandable apparatus placed radially adjacent to a thrombus;and b) acquiring an image of expanding the apparatus thereby increasingblood through the vessel wherein the increased blood flow partially orsubstantially dissolves the thrombus.

In still yet another embodiment, the method of invention is directed toa method for imaging dislodging a thrombus lodged in a blood vessel.This method comprises:

-   a) acquiring an image of a self-expandable apparatus placed radially    adjacent to a thrombus;-   b) acquiring an image of expanding the apparatus thereby engaging at    least a portion of the thrombus; and c) acquiring an image of moving    the apparatus distally or proximally thereby dislodging the    thrombus.

A number of self-expandable apparatus are contemplated to be useful inthe methods of the invention. In one embodiment, the apparatus isreversibly self-expandable. In another embodiment, the apparatus isfully retrievable or retractable. In one embodiment, the self-expandableapparatus comprises a mesh structure comprising a first plurality ofmesh cells, the mesh structure having a proximal end and a distal end; atapering portion comprising a second plurality of mesh cells, thetapering portion disposed toward the proximal end of the mesh structure;and a connection point, at which the tapering portion converges, locatedat a proximal end of the tapering portion, wherein the apparatus ispre-formed to assume a volume-enlarged form and, in the volume-enlargedform, takes the form of a longitudinally open tube tapering toward theconnection point.

Another embodiment of the invention is a self-expandable apparatus forremoval of a thrombus in a blood vessel, comprising: a mesh structurecomprising a first plurality of mesh cells, the mesh structure having aproximal end and a distal end wherein said distal end of the meshstructure is configured to engage at least a portion of the thrombus toform a removable, integrated apparatus-thrombus mass; a tapering portioncomprising a second plurality of mesh cells, the tapering portiondisposed toward the proximal end of the mesh structure; and a connectionpoint, at which the tapering portion converges, located at a proximalend of the tapering portion, wherein the apparatus is pre-formed toassume a volume-enlarged form and, in the volume-enlarged form, takesthe form of a longitudinally open tube tapering toward the connectionpoint.

It is contemplated that the distal end of the mesh structure isconfigured to assist in thrombus retrieval by providing increasingsupport to the mesh structure and by increasing thrombus retention.

In another embodiment of the invention is provided a removable,integrated apparatus-thrombus mass, comprising a thrombus at leastpartially engaged with an apparatus, wherein the apparatus comprises amesh structure comprising a first plurality of mesh cells, the meshstructure having a proximal end and a distal end wherein said distal endof the mesh structure is configured to engage at least a portion of thethrombus; a tapering portion comprising a second plurality of meshcells, the tapering portion disposed toward the proximal end of the meshstructure; and a connection point, at which the tapering portionconverges, located at a proximal end of the tapering portion, whereinthe apparatus is pre-formed to assume a volume-enlarged form and, in thevolume-enlarged form, takes the form of a longitudinally open tubetapering toward the connection point.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and constitutepart of this specification, illustrate exemplary embodiments of theinvention, and, together with the general description given above andthe detailed description given below, serve to explain the features ofthe invention.

FIG. 1 shows an apparatus useful for the methods of the presentinvention.

FIG. 2 a shows a target occlusion or thrombus to be treated by thepresent invention.

FIGS. 2 b, 3, and 4 show placement methods according to the presentinvention. FIG. 3 is shown with the microcatheter 8 in phantom.

FIG. 5 shows thrombus dislodgement and mobilization according to thepresent invention.

FIGS. 6 and 7 show thrombus dissolution methods according to the presentinvention.

FIGS. 8 and 9 show apparatus retrieval methods according to the presentinvention, with the microcatheter shown in phantom.

FIGS. 10, 11, and 12 show apparatus implantation methods according tothe present invention.

FIG. 13 is an apparatus according to one embodiment of the presentinvention having a honeycomb structure.

FIG. 14 is another embodiment of a stent according to the presentinvention having a honeycomb structure.

FIG. 15 is a third embodiment of a stent according to the presentinvention having a honeycomb structure.

FIG. 16 is a warp-knitted structure as can be used for an apparatusaccording to the invention.

FIG. 17 a and FIG. 17 b is a schematic representation of an apparatusaccording to an embodiment of the present invention shown in itssuperimposed and in its volume-reduced shape.

FIG. 18 a, FIG. 18 b, FIG. 18 c, FIG. 18 d, and FIG. 18 e areembodiments, including marker elements, that can be employed in the mostdistal segment of the apparatus according to the present invention.

FIG. 19 a and FIG. 19 b are schematic representations of two detachmentlocations by which the apparatus, according to the present invention,can be detachably linked to a guide wire.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications and patentapplications cited herein are incorporated herein by reference in theirentirety. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural references unless thecontext clearly dictates otherwise.

Methods

The invention is directed to methods of restoring localized flow to anoccluded vascular site. The vascular site, or blood vessel, can beoccluded by a thrombus. The apparatus employed in the methods of theinvention may be positioned at the vascular site with a microcatheterand optionally a guide catheter. The methods of the invention may employa fully retrievable apparatus which is an improvement over the art whichmethods required the apparatus to be implanted permanently into thepatient. When the apparatus is permanently placed in the patient,lifelong anticoagulant therapy for the patient is required. Therefore,it is contemplated that by using a retrievable apparatus, lifelonganticoagulant therapy may be avoided.

Methods and apparatus are provided to restore blood flow in cerebralarteries 11 occluded with thrombus 12 (FIG. 2 a). Such methods utilizean apparatus having a self-expandable, optionally reversiblyself-expandable, distal segment 1 including distal end 2, proximal end3, and body portion 4 that is pre-formed to assume a superimposedstructure 5 in an unconstrained condition but can be made to take on avolume-reduced form 6 making it possible to introduce it with a pushwire 7 attached at the proximal end 3 and a microcatheter 8, with thedistal segment 1 in its superimposed structure 5 assuming the form of alongitudinally open tube and having a mesh structure of interconnectedstrings or filaments or struts (FIGS. 1 and 3). In one embodiment, thedistal segment 1 has a tapering structure at its proximal end 3 wherethe strings or filaments or struts converge at a connection point 9. Thepush wire 7 is preferably attached at or adjacent to the connectionpoint 9. Such attachment 10 may be permanent or a releasable mechanism.The methods disclosed herein can be performed with the medical distalsegment 1 (or apparatus or stent, of which all terms are usedinterchangeably) described in U.S. Pat. No. 7,300,458, which isincorporated herein in its entirety.

According to the present invention, the self-expandable distal segment 1of the apparatus is positioned within a blood vessel 11 occluded bythrombus 12 in a volume-reduced form 6 by advancing it with the pushwire 7 within a microcatheter 8 such that its proximal end 3 is upstreamof the thrombus and its distal end 2 and is downstream of the thrombusand the body portion 4 is located radially adjacent to the thrombus 12(FIGS. 1 and 3). As shown in FIG. 3, the distal end 2 of the distalsegment 1 is positioned distal to the distal thrombus boundary and theproximal end 3 of the distal segment is positioned proximal of theproximal thrombus boundary. The distal segment 1 is held in a fixedposition by holding the push wire 7 stationary while the distal segment1 is released from its volume-reduced form 6 by withdrawing themicrocatheter 8 proximally of the distal segment 1 (FIG. 4). The distalsegment 1 assumes at least a portion of its superimposed structure 5 inits unconstrained condition 13 thereby expanding to bring at least partof the body portion into penetrating contact with the thrombus 12′,exerting an outward radial force on the thrombus 12′, reducing thecross-sectional area of the thrombus 12′, and immediatelyre-establishing blood flow 14 through the blood vessel 11 past thethrombus 12′.

Also contemplated by this invention is administration of an effectiveamount of a clot-busting drug, such as, for example tissue plasminogenactivator (tPA), to the site of the thrombus. Administration of thisdrug will act to further enhance dissolution of the clot.

This placement methodology expands the population of patients eligiblefor treatment over apparatus that require intravascular space distal tothe reach of a microcatheter as the methodology of this invention placesthe distal segment 1 beyond the distal end of the thrombus 12.Additionally, this placement methodology expands the population ofphysicians that can successfully practice the method, as it is deliveredwith microcatheter technology already familiar to the user, andfacilitates rapid placement of the apparatus. Immediately restoringblood flow 14 is a significant advantage over known apparatus andmethods for treating cerebral arteries 11 occluded by thrombus 12because known apparatus and methods may take hours to re-establish flow14, and it is well established that the risk and degree of permanentneurological deficit increases rapidly with increased time from onset ofsymptoms to blood flow restoration.

In one embodiment thrombus removal methods and apparatus are providedthat restore blood flow 14 in the occluded artery 11, with an increasedefficiency in dislodging the thrombus 12′ from the vessel coupled withremoval of the thrombus 12′ and apparatus from the patient. In apreferred embodiment, restoring blood flow 14 in the occluded artery 11involves placing a microcatheter 8 such that the distal tip 16 of themicrocatheter is beyond the distal end of the thrombus 12, wherein thedistal tip 16 is from greater than about 0 millimeter (mm) to about 10mm or more, or about 3 mm to about 5 mm (FIG. 2 b) beyond the distal endof the thrombus 12. The self-expandable distal segment 1 is advancedwithin the microcatheter 8 in its reduced volume form 6 by the push wire7 until its distal end 2 is just beyond the distal end of the thrombus12 (FIG. 3).

Visualization of proper placement may be done by fluoroscopy.Specifically, this may be accomplished by aligning radiopaque markers 15on the distal end of the distal segment with a distal radiopaquemicrocatheter marker 17 (FIG. 3). As mentioned above, this invention isalso directed to various methods of acquiring images of the process. Themethod of imaging typically employed is fluoroscopy (which can confirmproper placement of the apparatus) or contrast injection (which canconfirm blood flow restoration). However, a number of imaging methodsknown by those of skill in the art are also contemplated.

The distal segment 1 is then deployed within and across the thrombus 12′by holding the push wire 7 fixed while withdrawing the microcatheter 8proximally until the distal segment 1 is released 13 (FIG. 4). Oneindication of full deployment is the visualization by the clinician thata radiopaque marker 18 defining the proximal end 3 of the distal segment1 is aligned with, or distal of, the distal radiopaque microcathetermarker 17. Alternatively, the microcatheter 8 can be completely removedfrom the patient. Immediately upon distal segment 1 deployment 13, bloodflow 14 is restored across the thrombus 12′ and confirmation can bevisualized via contrast injection. This is an indication of properdistal segment position relative to the thrombus 12′ and vascularanatomy.

The apparatus can be used to remove the thrombus 12′ after one of thefollowing: a fixed amount of time has elapsed after deployment 13 of thedistal segment 1, which may be from about 0 minutes to about 120 minutesor more; blood flow 14 across the thrombus 12′ is observed to stop; apredetermined maximum amount of flow time has elapsed, whichever occursfirst.

Removing the thrombus 12′ may be accomplished by any number ofvariations (FIG. 5). For example, as the distal tip of volume-reducedform 6 is moved beyond the thrombus, it will encounter less resistanceto expansion and provide a greater radial force as compared to thatportion engaging the thrombus as shown in FIG. 5. Thus distal tip 2 mayexpand beyond the thrombus 12′ creating a distal tip 2 having a largerdiameter than the diameter of the distal segment that is engaged by atleast a portion of the thrombus. In some embodiments, this can be ahook-like distal configuration. Further structural modifications aredescribed below that could be used to further aid in thrombus engagementand removal. Using the push wire 7, a pull force 19 of the deployeddistal segment 13 will retract the thrombus back to the catheter as thehook-like configuration acts to snag the thrombus. Subsequent removal ofthe catheter will result in removal of the thrombus from the site ofocclusion.

Prior to pulling the apparatus back, the microcatheter 8 can bemanipulated in any of the following ways: the distal radiopaquemicrocatheter marker 17 can be left at or proximal to distal segmentproximal radiopaque marker 18 or completely removed from patient;microcatheter 8 can be moved forward to a predetermined point relativeto the distal segment 1, which may be: when the distal radiopaquemicrocatheter marker 17 is desirably aligned with the distal segment ofproximal radiopaque marker 18; when the distal radiopaque microcathetermarker 17 is desirably aligned distal of the distal segment of proximalradiopaque marker 18, for example about 0.5 mm to about 10 mm or about 5mm to about 10 mm; when significant resistance to microcatheter 8advancement is encountered as evidenced by buckling of the microcatheter8; or whichever of desired-alignment or significant resistance occursfirst. While moving the deployed distal segment 13 toward or into theguide catheter, any of the following may occur: proximal guide lumencommunicates with pressure bag or other positive pressure fluid source;proximal guide lumen communicates with atmosphere; or proximal guidelumen communicates with aspiration source or other negative pressure.

Thrombus removal methods of the present invention have unique advantagesover known thrombus removal methods. When deployed across a thrombus,the distal segment 1 creates intra-procedural flow 14 by creating afluid path across the thrombus 12′ (FIG. 4). In this way, the distalsegment 13 significantly reduces the pressure drop across the thrombus12′, and accordingly significantly reduces the pressure related forceswhich would otherwise resist removal of the thrombus 12 (FIG. 5).Further, the fluid path is created by the deployed distal segment 13separating a significant portion of the thrombus 12′ circumference awayfrom the vessel wall. In addition, expansion of volume-reduced form 6creates an integrated mass where the mesh is embedded within thethrombus. As above, the distal portion of volume-reduced form 6 canproduce a greater radial force (and may be in a hook-like configurationupon expansion) thereby facilitating removal of the thrombus.

It is estimated that about 10% to about 60% of the original thrombus 12circumference is separated from the vessel wall after the distal segment1 is deployed 13, and the ability of the post deployment thrombus 12′ tohang onto the vessel wall via adhesion and friction is accordinglyreduced. Still further, the cross sectional area of the originalthrombus 12 is significantly reduced by the deployed distal segment 13,resulting in a thrombus 12′ having about 30% to about 95% of itsoriginal cross sectional area, but more typically about 50% to about 80%of its original cross sectional area. All of this results in a moreeffective revascularization procedure as a result of lower thrombusdislodgement and mobilization force and more effective thrombusmobilization 19, as demonstrated by the functions later describedherein. Of further benefit, the lower thrombus mobilization force isdistributed along the entire length of the thrombus 12′, or at leastalong the entire length of the distal segment 13, reducing the chancesof the apparatus slipping past or through the thrombus or fragmentingthe thrombus, which could result in residual thrombus, distalembolization, or embolization of uninvolved territories.

A target occlusion is represented by an original thrombus 12 havingcross sectional area A (FIG. 2 a), creating an associated pressure dropacross the thrombus of P, having circumferential vessel contact area C,and f is a quantity proportional to a ratio of the thrombus adhesive andfrictional forces/contact area. The force required to dislodge ormobilize this thrombus by known methods that do not establishintra-procedural flow across the thrombus and do not separate asignificant portion of the thrombus circumference away from the vesselwall can be described by the function:(A*P)+C*f

For the thrombus removal methods of the present invention, that is whenthe distal segment 1 is deployed 13 within the thrombus 12′ (FIG. 4),the thrombus 12′ has reduced cross sectional area “a” where a<A, reducedpressure drop across the thrombus “p” where p<P, significantly reducedcircumferential vessel contact area “c” where c<C, and f is a quantityproportional to a ratio of the thrombus adhesive and frictionalforces/contact area. The force required to dislodge and mobilize thethrombus 12′ according to the methods described herein will besignificantly lower than forces required to dislodge and mobilizedoriginal thrombus 12 by known methods (FIG. 5), and can be described bythe function:(a*p)+c*f

Also contemplated by the present invention are thrombus dissolutionmethods and apparatus that restore blood flow 14 in the occluded artery,with an increased efficiency in dissolving part (FIG. 7) or all (FIG. 6)of the thrombus from the vessel and retrieval of the apparatus (FIGS. 8and 9). As previously described, the distal segment is deployed withinand across a thrombus 12′ to restore blood flow 14 in the occludedartery (FIG. 4). Immediately reestablishing blood flow 14 is asignificant advantage over know apparatus and methods for treatingcerebral arteries occluded by thrombus because known apparatus andmethods may take hours to reestablish flow. Specific benefits includereestablishing antegrade flow distal of the original occlusion toperfuse ischemic tissue and help break up emboli that may be presentdistal of the original occlusion. Additional benefit is derived fromincreasing the surface area of the thrombus 12′ exposed to the bloodflow, thereby improving the effectivity of natural lysing action of theblood on the thrombus 12′ and improving the effectivity of thethrombolytic, anti-coagulant, anti-platelet, or other pharmacologicalagents introduced by the physician, all of which facilitates thrombusdissolution. When the thrombus has been completely dissolved (FIG. 6),or sufficiently reduced 12″ such that reocclusion is not likely (FIG.7), the distal segment 1 is retrieved 20 by advancing the microcatheter8 over the entire distal segment 1 while holding the push wire 7 in afixed position such that the distal segment 1 is not moved axiallywithin the artery (FIGS. 8 and 9). The apparatus may then be removedthrough the microcatheter 8 or alternatively the microcatheter 8 can beremoved with the distal segment 1 of the apparatus still inside of it.

Additionally, it is contemplated that the methods of the presentinvention can restore blood flow in the occluded artery, with anincreased efficiency in dissolving part or all of the thrombus from thevessel and implantation of the distal segment 1. Methods that includeimplantation of the distal segment 1 require the use of an apparatuswith a releasable attachment mechanism between the distal segment 1 andpush wire 7. As previously described, the distal segment 1 is deployedwithin and across 13 a thrombus 12′ to restore blood flow 14 in theoccluded artery (FIG. 4). The distal segment 1 can then be released fromthe push wire via a releasable attachment mechanism. Such release mayoccur immediately upon reestablishing blood flow (FIG. 10), when thethrombus 12″ has been sufficiently reduced such that reocclusion is notlikely (FIG. 11), or when the thrombus is completely dissolved (FIG.12).

In another embodiment of the invention, the thrombus removal ordissolution is assisted by aspirating the microcatheter and/or the guidecatheter.

Utility derived from a releasable mechanism between the distal segmentand push wire includes suitability of one apparatus for all of themethods disclosed herein, providing procedural options for the user. Offurther benefit, a releasable mechanism enables the user to release theunconstrained distal segment if it is determined that removal from thepatient is not possible.

Certain embodiments of the invention include methods of restoring bloodflow and then detaching the apparatus and leaving the apparatus in situ(FIG. 12). This can be done when it is determined by the clinician thateither the apparatus is no longer retrievable. In this embodiment, it iscontemplated that the apparatus would be coated or otherwise embeddedwith anticoagulant or antiplatelet drugs. This is more thoroughlydiscussed below.

Apparatus

As mentioned above, any suitable self-expandable apparatus may beemployed by the methods of the invention. Various embodiments of theapparatus may be found in U.S. Pat. No. 7,300,458, which is incorporatedby reference in its entirety.

A distal segment 1, according to FIG. 13, consists of a mesh orhoneycomb structure that, in one embodiment, comprises a multitude offilaments interconnected by a laser welding technique. The distalsegment 1 can be subdivided into a functional structure A and a taperingproximal structure B, the two structures being distinguishable, interalia, by a different mesh size. To enable the functional structure A toperform its function, its mesh cells 23 are held relatively narrow sothat they lend themselves to the implantation into the thrombus 12. Ingeneral, the mesh width is in the range of 0.5 to 4 mm and may varywithin the segment.

In one aspect of the present invention, the distal segment 1 is a flator two-dimensional structure that is rolled up to form a longitudinallyopen object capable of establishing close contact with the wall of thevessel into which it is introduced.

In the tapering proximal structure B of the distal segment 1, there isprovided a wider mesh cell 24 structure which has been optimized towardshaving a minimum expansion effect. In the area of the tapering structure22, the filaments have a greater thickness and/or width to be able tobetter transfer to the functional structure A the thrust and tensileforces of the guide wire exerted at a connection point 9 when the distalsegment 1 is introduced and placed in position. In the area of thetapering structure it is normally not necessary to provide support for,and coverage of, the vessel wall, but on the other hand requirements asto tensile and thrust strength increase. The filament thickness in thefunctional structure A generally ranges between 0.02 and 0.076 mm, andin proximal structure part B, the filament thickness is greater than0.076 mm.

The proximal structure forms an angle from 45 degrees to 120 degrees atthe connection point 9, in particular an angle of about 90 degrees. Thefilament thickness (or string width) is the same as the mesh size andits shape may vary over a great range to suit varying requirements as tostability, flexibility and the like. It is understood that the proximalstructure B, as well, contacts the vessel wall and thus does notinterfere with the flow of blood within the vessel.

At a distal end, the filaments 22 end in a series of tails 2 that are ofsuitable kind to carry platinum markers that facilitate the positioningof the distal segment 1.

The distal segment 1 is curled up in such a way that edges 27 and 28 areat least closely positioned to each other and may overlap in the area ofthe edges. In this volume-reduced form, the distal segment 1, similar toa wire mesh roll, has curled up to such an extent that the roll soformed can be introduced into a microcatheter and moved within thecatheter. Having been released from the microcatheter, the curled-upstructure springs open and attempts to assume the superimposed structurepreviously impressed on it and in doing so closely leans to the innerwall of the vessel to be treated, thus superficially covering a thrombusand then implanting into the thrombus that exists in that location. Inthis case the extent of the “curl up” is governed by the vessel volume.In narrower vessels a greater overlap of the edges 27 and 28 of thedistal segment 1 will occur whereas in wider vessels the overlap will besmaller or even “underlap,” will be encountered, and due care must beexercised to make sure the distal segment 1 still exhibits a residualtension.

Suitable materials that can be employed in the device include alloyshaving shape-memory properties. The finished product is subjected to atempering treatment at temperatures customarily applied to the materialso that the impressed structure is permanently established.

The distal segment 1 has a mesh-like structure consisting of strings orfilaments connected with each other. Strings occur if the distal segment1 comprises cut structures as, for example, are frequently put to use incoronary stents, a mesh-like structure consisting of filaments is foundif the distal segment 1 is present in the form of mats having knitted orbraided structures or in the form of individual filaments that arewelded to one another.

FIG. 14 shows another embodiment of a distal segment 1 according to theinvention having the above described honeycomb structure where thetapering proximal structure B is connected with the functional structurepart A by additional filaments 29 in a peripheral area 30 as well as inthe central area. The additional filaments 29 and 30 bring about a moreuniform transmission of the tensile and thrust forces from the proximalstructure B to the functional structure A. As a result, the tensileforces can be better transmitted, especially if the stent might have tobe repositioned by having to be retracted into the microcatheter. Theadditional filaments 29, 30 facilitate the renewed curling up of thestent. Similarly, the transmission of thrust forces occurring when thestent is moved out and placed in position is facilitated so that thestent can be gently applied.

FIG. 15 shows another embodiment of a distal segment 1 according to theinvention having a honeycomb structure with the edges 27 and 28 beingformed of straight filaments 29. According to this embodiment, thethrust or pressure exerted by the guide wire at the connection point 9is directly transmitted to the edges 27 and 28 of the functionalstructure part A which further increases the effect described withreference to FIG. 14.

The embodiment as per FIG. 15, similar to those depicted in FIGS. 13 and14, may be based on a cut foil, i.e., the individual filaments 22, 29and 30 are substituted by individual strings being the remainingelements of a foil processed with the help of a cutting technique. Lasercutting techniques for the production of stents having a tubularstructure are known. The processing of a foil for the production of apattern suitable for a stent is performed analogously. The impression ofthe superimposed structure is carried out in the same way as is used forthe filament design.

In one embodiment, expanded metal foil may be used with the respectivestring widths being of the same magnitude. In one embodiment, it isenvisioned to subsequently smooth the foil to make sure all strings arearranged on the same plane. The thickness of the foil usually rangesbetween 0.02 and 0.2 mm. Foils of greater thickness also permit thestent to be used in other fields of application, for example, ascoronary stents or in other regions of the body including, for instance,the bile duct or ureter.

Foils worked with the help of a cutting technique are finished byelectrochemical means to eliminate burrs and other irregularities toachieve a smooth surface and round edges. One of ordinary skill in theart will understand these electrochemical processes as these processesalready are in use in medical technology. In this context, it is to benoted that the stents according to the invention that are based on atwo-dimensional geometry and on which a three-dimensional structure isimpressed subsequently can be manufactured and processed more easilythan the conventional “tubular” stents that already, during manufacture,have a three-dimensional structure and necessitate sophisticated andcostly working processes and equipment.

As pointed out above, the mesh structure of the distal segment 1according to the invention may consist of a braiding of individualfilaments. Such a knitted structure is shown in FIG. 16 where theindividual filaments 22 are interwoven in the form of a “single jerseyfabric” having individual loops 23 forming a mesh-like structure 31.Single jersey goods of this type are produced in a known manner from arow of needles. The single jersey goods have two fabric sides ofdifferent appearance, i.e., the right and left side of the stitches. Asingle jersey fabric material features minor flexibility in a transversedirection and is very light.

Filaments consisting of a braid of individual strands and formed into arope can also be employed. Braids comprising twelve to fourteen strandshaving a total thickness of 0.02 mm can be used. Platinum, platinumalloys, gold and stainless steel can be used as materials for thefilaments. Generally speaking, all permanent distal segment 1 materialsknown in medical technology can be employed that satisfy the relevantrequirements.

In one embodiment, it is advantageous to have the fabric rims of such aknitted structure curling up as is known, for example, from theso-called “Fluse” fabric, a German term, which is of benefit withrespect to the superimposed structure and application dealt with here.In this case, the superimposed structure can be impressed by means ofthe knitting process. However, the use of shape-memory alloys in thiscase as well is feasible and useful.

For the production of such knitted structures, known knitting processesand techniques can be employed. However, since the distal segmentsaccording to the invention are of extremely small size—for example, asize of 2 by 1 cm—it has turned out to be beneficial to produce thedistal segments in the framework of a conventional warp or weft knittingfabric of textile, non-metallic filaments, for example, in the form of arim consisting of the respective metallic filaments from which the weftor warp knitting fabric either starts out or that extends from such afabric. The arrangement of the metallic part of the weft or warpknitting fabric at the rim achieves the aforementioned curling effect.The non-metallic portions of the knitted fabric are finally removed byincineration, chemical destruction or dissolution using suitablesolvents.

FIG. 1 shows a combination of a guide wire 7 with the distal segment 1attached to it that consists of filaments connected to each other bywelding. The distal ends 2 and the connection point 9 where thefilaments of the distal segment 1 converge in a tapering structure andthat simultaneously represents the joining location with guide wire 7are shown. The guide wire 7 is introduced into a microcatheter 8 whichis of customary make.

Shifting the guide wire 7 within the catheter 8 will cause the distalsegment 1 to be pushed out of or drawn into the catheter. Upon the stentbeing pushed out of the microcatheter 8 the mesh-like structure attemptsto assume the superimposed shape impressed on it, and when being drawnin, the mesh structure folds back into the microcatheter 8 adapting tothe space available inside.

As a result of the stiffness of its mesh structure, the distal segment 1can be moved to and fro virtually without restriction via the guide wire7 until it has been optimally positioned within the vessel system.

As mentioned earlier, customary microcatheters can be used. Oneadvantage of the distal segment 1 according to the invention and of thecombination of distal segment 1 and guide wire according to theinvention is, however, that after having placed the microcatheter inposition with a customary guide wire/marker system, the combination ofguide wire 7 and distal segment 1 according to the invention can beintroduced into the microcatheter, moved through it towards theimplantation site and then moved out and applied in that position.Alternatively, it will be possible to have a second microcatheter ofsmaller caliber accommodate guide wire 7 and distal segment 1 and withthis second microcatheter within the firstly positioned microcathetershift them to the implantation site. In any case, the distal segment 1can be easily guided in both directions.

FIG. 17 shows a schematic representation of an distal segment 1according to the invention in its superimposed or volume-expanded shapeand in its volume-reduced shape. In its expanded shape, as illustratedin FIG. 17 a, the distal segment 1 forms a ring-shaped structure withslightly overlapping edges 27 and 28. In FIG. 17 a the distal segment 1is viewed from its proximal end as a top view with the connection point9 being approximately positioned opposite to the edges 27 and 28. In thecombination according to the invention, the guide wire 7 is affixed atthe connection point 9.

FIG. 17 b shows the same distal segment 1 in its volume-reduced form 6as it is arranged, for example, in a microcatheter in a curled upcondition. In the case illustrated there is a total of two windings ofthe curled-up distal segment 1 with the connection point 9 being locatedat the proximal side and the two lateral edges 27 and 28 being thestarting and final points of the roll or spiral. The structure is heldin its volume-reduced form by the microcatheter 8 and when the distalsegment 1 is pushed out of the microcatheter 8 it springs into itsexpanded shape, as illustrated by FIG. 17 a, similar to a spiral spring.

FIG. 18 a shows a marker element 15 suitable for the distal segment 1according to the invention with the marker element 15 being capable ofbeing arranged at the distal end of the distal segment 1. The markerelement 15 consists of a lug 33 provided with a small marker plate 35levelly arranged inside it, i.e., flush with the plane of the distalsegment 1 without any projecting elements. The plate 35 is made of anX-ray reflecting material, for example, platinum or platinum-iridium.The marker plate 35 may be connected to the surrounding distal segment 1structure by known laser welding techniques. As shown in FIG. 18 b, themarker elements 15 are arranged at the distal end of the distal segment1.

As mentioned above, in one embodiment, the apparatus is configured to soas to provided a removable, integrated thrombus apparatus-mass. Thisconfiguration can be done in a variety of ways. For example, as can beseen in FIG. 18 c, marker element 15′ can be provided in a spiralthereby increasing the support of the distal end of the mesh structureand aiding in the thrombus retrieval. Also, as seen in FIG. 18 d, themarker element 15″ can be provided as an eyelet shape functioning in amanner similar to the spiral marker 15′. FIG. 18 e shows a markerelement 15′″ shown in the shape of a hook or a peg which can be added toprovide additional retention of the thrombus during removal. Markerelement 15′″ is optionally radiopaque or may be made from the same shapememory alloy as the mesh structure.

Additional structural configurations contemplated to provide a removal,integrated thrombus apparatus-mass include: 1) a greater diameter of themesh structure in the most distal location of the distal segment 1compared to the proximal end of the mesh structure (or a widening-taperon the distal end of the distal segment 1); 2) a third plurality of meshcells located in the most distally in the distal segment 1, wherein thethis third plurality of mesh cells have smaller mesh size compared tothe first plurality of mesh cells; 3) adding synthetic polymers orpolymeric fibers to the mesh structure; and 4) heating the distal end ofthe distal segment 1 for a time sufficient to impart increased radialstrength for better thrombus retention.

As mentioned above, fibers may be added to the mesh structure. Fibersmay be wrapped or wound around the mesh structure. They may have looseends or may be fully braided throughout the distal segment 1.

Suitable fibers are taught in US Publication 2006/0036281, which isincorporated by reference in its entirety. In certain embodiments, thefibers may be comprised of polymeric materials. The polymeric materialsmay include materials approved for use as implants in the body or whichcould be so approved. They may be nonbiodegradable polymers such aspolyethylene, polyacrylics, polypropylene, polyvinylchloride, polyamidessuch as nylon, e.g., Nylon 6.6, polyurethanes, polyvinylpyrrolidone,polyvinyl alcohols, polyvinylacetate, cellulose acetate, polystyrene,polytetrafluoroethylene, polyesters such as polyethylene terephthalate(Dacron), silk, cotton, and the like. In certain specific embodimentsthe nonbiodegradable materials for the polymer component may comprisepolyesters, polyethers, polyamides and polyfluorocarbons.

The polymers can be biodegradable as well. Representative biodegradablepolymers include: polyglycolic acid/polylactic acid (PGLA),polycaprolactone (PCL), polyhydroxybutyrate valerate (PHBV),polyorthoester (POE), polyethyleneoxide/polybutylene terephthalate(PEO/PBTP), polylactic acid (PLA), polyglycolic acid (PGA), poly(p-dioxanone), poly (valetolactone), poly (tartronic acid), poly (βmalonic acid), poly (propylene fumarate), poly (anhydrides); andtyrosine-based polycarbonates. Additional polymers contemplated includepolyglycolide and poly-L-lactide.

Other equivalent materials, including but not limited to stereoisomersof any of the aforementioned, may be used as well.

FIGS. 19 a and 19 b are representations, respectively, of two variationsof a separating arrangement by which the distal segment 1 according tothe invention is detachably connected to a guide wire 7. In each case, aseparating arrangement consists of a dumb-bell shaped element 43 thatdissolves under the influence of electrical energy when in contact withan electrolyte. At the proximal (guidewire side) end of the dumb-bellshaped separating element 43, as per FIG. 19 a, a spiral structure 45 islocated that interacts with a strengthening spiral 46 of the guide wire7. At the distal end, a ball-shaped element 47 is arranged that, withthe help of a laser welding technique, is connected to a platinum spiral48 which, in turn, is linked with the connection point 9 situated at theproximal end of the distal segment 1. The platinum spiral 48 also servesas an X-ray reflecting proximal marker of the distal segment 1.

To strengthen the joint between the ball-shaped element 47 and theconnection point 9, a reinforcement wire 49 may be provided.Alternatively, the platinum spiral 48 may also be designed in such amanner that it withstands the tensile and thrust forces imposed on it.

The separating element 43 can include a steel material that issusceptible to corrosion in an electrolyte under the influence ofelectrical energy. To accelerate corrosion and shorten the separatingtime span, a structural or chemical weakening of the dumb-bell shapedelement 43 may be beneficial, for example, by applying grinding methodsor thermal treatment.

Generally, the portion of the dumb-bell 43 accessible to the electrolytehas a length of 0.1 to 0.5 mm, particularly 0.3 mm.

The spiral structure 45 is secured via welding both to the dumb-bellshaped element 43 and the reinforcement spiral 46 of the guide wire 7.The guide wire 7 itself is slidably accommodated within themicrocatheter 8.

FIG. 19 b shows a second embodiment that differs from the one describedwith respect to FIG. 19 a, in that the dumb-bell shaped element 43 has aball-shaped element 47 at each end. The ball shaped elements 47 areconnected distally to the connection point 9 of the distal segment 1 andproximally to the guide wire 7 via spirals 48, 46, respectively.

It is of course also provided that other separating principles may beapplied, for example, those that are based on mechanical principles ormelting off plastic connecting elements.

Coated Apparatus

This invention also contemplates coating the apparatus withanticoagulant and/or an antiplatelet agent or drug. It is contemplatedthat a drug may be used alone or in combination with another drug.

Anticoagulant agents or anticoagulants are agents that prevent bloodclot formation. Examples of anticoagulant agents include, but are notlimited to, specific inhibitors of thrombin, factor IXa, factor Xa,factor XI, factor XIa, factor XIIa or factor VIIa, heparin andderivatives, vitamin K antagonists, and anti-tissue factor antibodies,as well as inhibitors of P-selectin and PSGL-1. Examples of specificinhibitors of thrombin include hirudin, bivalirudin (Angiomax®),argatroban, ximelagatran (Exanta®), dabigatran, and lepirudin(Refludan®). Examples of heparin and derivatives include unfractionatedheparin (UFH), low molecular weight heparin (LMWH), such as enoxaparin(Lovenox®), dalteparin (Fragmin®), and danaparoid (Orgaran®); andsynthetic pentasaccharide, such as fondaparinux (Arixtra®), idraparinuxand biotinylated idraparinux. Examples of vitamin K antagonists includewarfarin (Coumadin®), phenocoumarol, acenocoumarol (Sintrom®),clorindione, dicumarol, diphenadione, ethyl biscoumacetate,phenprocoumon, phenindione, and tioclomarol.

Antiplatelet agents or platelet inhibitors are agents that block theformation of blood clots by preventing the aggregation of platelets.There are several classes of antiplatelet agents based on theiractivities, including, GP IIb/IIIa antagonists, such as abciximab(ReoPro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®); P2Y₁₂receptor antagonists, such as clopidogrel (Plavix®), ticlopidine(Ticlid®), cangrelor, ticagrelor, and prasugrel; phosphodiesterase III(PDE III) inhibitors, such as cilostazol (Pletal®), dipyridamole(Persantine®) and Aggrenox® (aspirin/extended-release dipyridamole);thromboxane synthase inhibitors, such as furegrelate, ozagrel, ridogreland isbogrel; thromboxane A2 receptor antagonists (TP antagonist), suchas ifetroban, ramatroban, terbogrel,(3-{6-[(4-chlorophenylsulfonyl)amino]-2-methyl-5,6,7,8-tetrahydronaphth-1-yl}propionicacid (also known as Servier S 18886, by de Recherches InternationalesServier, Courbevoie, France); thrombin receptor antagonists, such asSCH530348 (having the chemical name of ethyl(1R,3aR,4aR,6R,8aR,9S,9aS)-9-(E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1-methyl-3-oxododecahydronaphtho[2,3-C]furan-6-ylcarbamate,by Schering Plough Corp., New Jersey, USA, described in US2004/0192753A1and US2004/0176418A1 and studied in clinical trials, such as AMulticenter, Randomized, Double-Blind, Placebo-Controlled Study toEvaluate the Safety of SCH 530348 in Subjects Undergoing Non-EmergentPercutaneous Coronary Intervention with ClinicalTrials.gov Identifier:NCT00132912); P-selectin inhibitors, such as2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylicacid (also known as PSI-697, by Wyeth, N.J., USA); and non-steroidalanti-inflammatory drugs (NSAIDS), such as acetylsalicylic acid(Aspirin®), resveratrol, ibuprofen (Advil®, Motrin®), naproxen (Aleve®,Naprosyn®), sulindac (Clinoril®), indomethacin (Indocin®), mefenamate,droxicam, diclofenac (Cataflam®, Voltaren®), sulfinpyrazone (Anturane®),and piroxicam (Feldene®). Among the NSAIDS, acetylsalicylic acid (ASA),resveratrol and piroxicam are preferred. Some NSAIDS inhibit bothcyclooxygenase-1 (cox-1) and cyclooxygenase-2 (cox-2), such as aspirinand ibuprofen. Some selectively inhibit cox-1, such as resveratrol,which is a reversible cox-1 inhibitor that only weakly inhibits cox-2.

In one embodiment, a controlled delivery of the drug can control thelytic effect of the drug and treat ischemic stroke and many othervascular diseases. The release rate can be controlled such that about50% of the drug can be delivered to the thrombus in from about 1 toabout 120 minutes. This controlled delivery can be accomplished in oneor more of the following ways. First, the drug and polymer mixture maybe applied to the stent and the amount of polymer may be increased orthe combination may be applied in a thicker layer. Second, the stent maybe first coated with polymer, then coated with a layer of drug andpolymer, and then a topcoat of polymer can be applied. The release ratesof the drug can be altered by adjusting the thickness of each of thelayers. Third, the stent can be manufactured to provide reservoirs tohold the drug. In this embodiment, the drug is filled in smallreservoirs made on the stent surface. Reservoirs can be made by lasercutting, machine electro-chemical, mechanical or chemical processing.

In the embodiments just described the polymer is biocompatible andbiodegradable. These polymers are well known in the art.

Additionally, stents can be coated with a drug-eluting coating such as acombination of a polymer and a pharmaceutical agent. Such coatings canbe applied using methods well established in the art, such as dipping,spraying, painting, and brushing. See, U.S. Pat. Nos. 6,214,115;6,153,252; U.S. Patent Application No. 2002/0082679; U.S. Pat. Nos.6,306,166; 6,517,889; 6,358,556; 7,318,945; 7,438,925.

For example, Chudzik et al. (U.S. Pat. No. 6,344,035) teaches a methodwherein a pharmaceutical agent or drug is applied in combination with amixture of polymers such as poly(butyl methacrylate) andpoly(ethylene-co-vinyl acetate). Guruwaiya et al. discloses a method forcoating a stent wherein a pharmacological agent is applied to a stent indry, micronized form over a sticky base coating (U.S. Pat. No.6,251,136). Ding et al. teaches a method of applying drug-releasepolymer coatings that uses solvents (U.S. Pat. No. 5,980,972) whereinthe solutions are applied either sequentially or simultaneously onto thedevices by spraying or dipping to form a substantially homogenouscomposite layer of the polymer and the pharmaceutical agent.

Although various exemplary embodiments of the present invention havebeen disclosed, it will be apparent to those skilled in the art thatchanges and modifications can be made which will achieve some of theadvantages of the invention without departing from the spirit and scopeof the invention. It will be apparent to those reasonably skilled in theart that other components performing the same functions may be suitablysubstituted.

We claim:
 1. A self-expandable apparatus for removal of a thrombus in ablood vessel, comprising: a tubular structure having a proximal end anda distal end, the structure having (a) a distal portion comprising afirst plurality of cells, (b) a proximal portion comprising a secondplurality of cells,(c) a first diameter at the distal end, and (d) asecond diameter at the proximal end, the distal portion having adistally widening taper at a distal end portion of the distal portionsuch that the first diameter is greater than the second diameter, theapparatus further comprising a connection point located at a proximalend of the proximal portion wherein the proximal portion converges atthe connection point, the apparatus further comprising two edgesextending parallel to a longitudinal axis of the structure, wherein thestructure is configured to assume an expanded configuration at the placeof implantation, and wherein the structure is configured to be modifiedinto a volume-reduced configuration for insertion within amicrocatheter, the volume-reduced configuration having a smallercross-sectional dimension than the expanded configuration, the two edgesbeing overlapped in the volume-reduced configuration, wherein thestructure is configured to expand into the thrombus when transitioningfrom the volume-reduced configuration to the expanded configuration. 2.The apparatus of claim 1, wherein the distal end of the structurecomprises radiopaque markers having a spiral or eyelet shape.
 3. Theapparatus of claim 1, wherein the distal end of the structure is bentand extends distally at an acute angle relative to the longitudinal axisof the structure.
 4. The apparatus of claim 1, the structure comprisinga first plurality of cells at a proximal portion, a second plurality ofcells at a tapered portion, and wherein the distal end of the structurecomprises a third plurality of cells and wherein said third plurality ofcells has a smaller cell size than the second plurality of cells.
 5. Theapparatus of claim 1, wherein the distal end of the structure comprisesone or more pegs and/or hooks.
 6. The apparatus of claim 1, wherein thedistal end of the structure further comprises the addition of syntheticfibers.
 7. The apparatus of claim 1, wherein the distal end of thestructure has been heated for a sufficient time to provide increasedradial strength.
 8. The apparatus of claim 1, wherein the structure iscoated with an anticoagulant or antiplatelet drug.
 9. The apparatus ofclaim 8, wherein the structure is further coated with a biodegradable,biocompatible polymer to provide for sustained release of theanticoagulant or antiplatelet drug.
 10. The apparatus of claim 1,wherein the structure comprises reservoirs to hold an anticoagulant orantiplatelet drug.